Review
published: 16 April 2018
Edited by:
Annemieke Boots,
University Medical Center
Groningen, Netherlands
Reviewed by:
Ana Maria Teixeira,
University of Coimbra, Portugal
Emily C. LaVoy,
University of Houston,
United States
*Correspondence:
John P. Campbell
j.campbell@bath.ac.uk;
James E. Turner
j.e.turner@bath.ac.uk
Specialty section:
This article was submitted
to Inflammation,
a section of the journal
Frontiers in Immunology
Received: 19 November 2017
Accepted: 15 March 2018
Published: 16 April 2018
Citation:
Campbell JP and Turner JE (2018)
Debunking the Myth of Exercise-
Induced Immune Suppression:
Redefining the Impact of Exercise
on Immunological Health
Across the Lifespan.
Front. Immunol. 9:648.
doi: 10.3389/fimmu.2018.00648
Frontiers in Immunology  |  www.frontiersin.org
doi: 10.3389/fimmu.2018.00648
Debunking the Myth of Exercise-
Induced Immune Suppression:
Redefining the Impact of Exercise
on Immunological Health Across
the Lifespan
John P. Campbell* and James E. Turner*
Department for Health, University of Bath, Bath, United Kingdom
Epidemiological evidence indicates that regular physical activity and/or frequent
structured exercise reduces the incidence of many chronic diseases in older age,
including communicable diseases such as viral and bacterial infections, as well as non-
communicable diseases such as cancer and chronic inflammatory disorders. Despite
the apparent health benefits achieved by leading an active lifestyle, which imply that
regular physical activity and frequent exercise enhance immune competency and regu-
lation, the effect of a single bout of exercise on immune function remains a controversial
topic. Indeed, to this day, it is perceived by many that a vigorous bout of exercise can
temporarily suppress immune function. In the first part of this review, we deconstruct
the key pillars which lay the foundation to this theory—referred to as the “open window”
hypothesis—and highlight that: (i) limited reliable evidence exists to support the claim
that vigorous exercise heightens risk of opportunistic infections; (ii) purported changes
to mucosal immunity, namely salivary IgA levels, after exercise do not signpost a period
of immune suppression; and (iii) the dramatic reductions to lymphocyte numbers and
function 1–2  h after exercise reflects a transient and time-dependent redistribution
of immune cells to peripheral tissues, resulting in a heightened state of immune sur-
veillance and immune regulation, as opposed to immune suppression. In the second
part of this review, we provide evidence that frequent exercise enhances—rather than
suppresses—immune competency, and highlight key findings from human vaccination
studies which show heightened responses to bacterial and viral antigens following bouts
of exercise. Finally, in the third part of this review, we highlight that regular physical
activity and frequent exercise might limit or delay aging of the immune system, providing
further evidence that exercise is beneficial for immunological health. In summary, the
over-arching aim of this review is to rebalance opinion over the perceived relationships
between exercise and immune function. We emphasize that it is a misconception to label
any form of acute exercise as immunosuppressive, and, instead, exercise most likely
improves immune competency across the lifespan.
Keywords: exercise, physical activity, upper respiratory tract infections, open window hypothesis, infection
susceptibility, ageing, immunosenescence, immune competency
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Campbell and Turner
INTRODUCTION
Lifelong physical activity1 is a potent means of reducing the
risk of non-communicable diseases including cancer, car-
diovascular disease, and other chronic inflammatory disorders
(1). Evidence also shows that a physically active lifestyle
diminishes the risk of contracting a range of communicable
diseases including viral and bacterial infections (2–6). In
contrast to the widely accepted long-term health benefits that
are achieved by regular physical activity, which imply that
immune competency and regulation are improved by frequent
exercise bouts, the effect of a single bout of exercise on immune
function remains hotly disputed. Undeniably, acute vigorous
exercise has a profound effect on the phenotypic makeup and
functional capacity of the immune system. Indeed, the behav-
ior of almost all immune cell populations in the bloodstream is
altered in some way during and after exercise (7, 8). However,
for decades, it has been widely accepted that these changes
result in a temporary decline in immune competency in the
hours following exercise. In the first part of this review, we
re-interpret these data and strive to dispel the misconception
that an acute bout of exercise is detrimental to immunological
health. In the second part of this article, we demonstrate that
rather than suppressing immunity, contemporary evidence
shows that an acute bout of exercise improves immune sur-
veillance, for example leading to enhanced antibacterial and
antiviral immunity. Finally, in the third part of this article, we
summarize recent data suggesting that regular physical activity
and frequent exercise, which reduces systemic inflammatory
activity and improves aspects of immune function, also leads to
alterations in classical biomarkers of an aging immune system.
These changes could be interpreted as limiting or delaying
immunological aging (9–13).
PART A: IS IT TIME TO CLOSE THE
SHUTTERS ON THE “OPEN-WINDOW”
HYPOTHESIS? A BOUT OF EXERCISE
DOES NOT SUPPRESS IMMUNE
COMPETENCY
A prevailing myth has formed in the literature that participating in
an acute bout of aerobic exercise, particularly if it is vigorous and
prolonged, can be detrimental to immune competency. The foun-
dations of this belief lay in research publications emanating from
1 
“Physical activity” refers to activities undertaken during leisure time, at home,
as part of employment, or for transport purposes. “Exercise” is a component of
physical activity within the leisure time domain and refers to physical activities that
are planned, structured, repetitive, and undertaken for the purpose of improving or
maintaining components of physical fitness and/or sporting performance. When
individuals are referred to as being “active” or “inactive,” the description infers that
these people undertake (or fail to undertake) a defined level of exercise or physical
activity (e.g., age-specific physical activity recommendations, such as those pub-
lished by the World Health Organisation). In this review, the term “exercise” will
generally be used to describe the effects that active behaviours have on immune
competency. Individuals described as being “sedentary” accumulate prolonged
periods of behaviour eliciting low energy expenditure (e.g. sitting and lying).
Frontiers in Immunology  |  www.frontiersin.org
Exercise, Health, and Immunity Across the Lifespan
the 1980s and 1990s, reviewed extensively elsewhere (7, 8, 14).
Findings from these early studies led to three principles of exer-
cise immunology being formed, which have, until now, generally
been unchallenged in the literature: (i) infection risk is increased
after an acute bout of prolonged and vigorous aerobic exercise;
(ii) acute bouts of vigorous exercise can lead to a temporary
reduction to salivary IgA levels culminating in a higher risk
of opportunistic infections; and (iii) transient decreases in the
number of peripheral blood immune cells, which occurs in the
hours following vigorous exercise, represents a period of immune
suppression. Over the years, these collective observations have
coalesced and led to the creation of the so-called “open-window”
hypothesis, which purports that the immune system is compro-
mised in the hours after vigorous exercise, leading to an increased
risk of opportunistic infections in the days thereafter. To this
day, the “open window” hypothesis continues to be discussed
(15), despite the existence of contradictory evidence. Here, in
the first part of this review, we aim to dispel the “open-window”
hypothesis by revisiting key research studies and highlighting
that limited evidence exists to support each of the three pillars
that lay its foundation.
Exercise and Opportunistic Infections
It has been speculated for over a century that participation
in physical activity heightens the risk of opportunistic infec­
tions (16). However, deeper investigation into the relationship
between exercise and infection susceptibility did not take place
until the end of the twentieth century. At this juncture, the
principle focus of many of these studies in the late 1980s and
early 1990s was to determine whether infection incidence was
increased in elite and recreational athletes in the weeks fol-
lowing mass participation distance running events. One of the
first studies from this era found that one third of 150 runners
participating in the 1982 Two Oceans 56 km ultramarathon in
Cape Town South Africa self-reported symptoms of upper res-
piratory tract infections (URTIs; symptoms = runny nose, sore
throat, sneezing) within 2  weeks of the race (17). The control
group, who were age matched and shared a home with another
of the race competitors, reported only half the amount of URTIs
in the same period (17). Similar observations were made in an
often-cited larger study of the 1987 Los Angeles Marathon (18).
Of 2,311 respondents who had completed the marathon and
whom did not report an infection in the week prior to the race,
12.9% reported an infection in the week after the race compared
to only 2.2% of individuals who withdrew from the race for
reasons other than illness (odds ratio of infection in runners
versus non-runners = 5.9). A separate study conducted around
the same time found that shorter duration running events, such
as 5, 10 km, and half-marathons (21 km) did not appear to elicit
an increased incidence of self-reported URTIs (19), thereby
suggesting that URTI symptoms are increased only when the
duration of the exercise is long.
A fundamental limitation of each of the aforementioned
studies is that none of the self-reported infections were clinically
confirmed by laboratory analyses (e.g., molecular or microbio-
logical techniques, such as polymerase chain reaction or bacte-
rial cultures). As a consequence, it was questioned whether the
2 April 2018 | Volume 9 | Article 648
Campbell and Turner
self-reported URTIs in these studies represented genuine infec-
tions. Clarifying this issue, a study employing nasopharyngeal
and throat swabs in athletes who reported URTI symptoms over
a 5-month period—including periods of competition—found
that few of the self-reported infections were of bacterial, viral,
chlamydial, or mycoplasmal nature (20). Indeed, of 37 episodes
of URTI reported by athletes in this study, only 11 of these
(30%) had a positive laboratory diagnosis. These findings place
the previously discussed marathon studies in a different light
(17, 18) and open the possibility that many of the URTIs reported
were a symptom of other non-infectious causes. Indeed, of the
of the non-infectious “URTIs” reported by Spence et  al. (20),
and likely captured elsewhere (17, 18), it is proposed that these
symptoms are a result of other causes, including allergy and
asthma, non-specific mucosal inflammation, or airway epithe-
lial cell trauma due to increased ventilation or exposure to cold
air (21). In the few cases of clinically confirmed URTIs, these
appear to be from viruses—in particular rhinoviruses (i.e., the
“common cold”)—rather than bacterial infection (20, 22), which
is in line with the typical incidence and etiology of infections at
the population level (23).
In the previously discussed clinical laboratory study of infec-
tion incidence in athletes (20), it is notable that the proportion of
athletes with a confirmed infection during the 5-month period
was as follows: 2/20 controls (10%), 3/31 (10%) recreational
athletes, and 6/32 (19%) elite athletes. Although this study was
small, these data appear to align with observations from earlier
self-report studies which found that the incidence of URTI symp-
toms was higher in those with the fastest race time and those who
had completed a greater training volume pre-race (17, 18). These
early observations contributed to the formulation of the “J-shaped
curve” (24). This hypothesis infers that those who undertake an
excessive volume of exercise, over a period of weeks and months,
sometimes referred to as “over-training” or “intensified training”
(25, 26), are at a greater risk of infections (24). In this scenario,
other factors present prior to an acute bout of exercise, such as
psychological stress and anxiety (27–29), or nutritional deficien-
cies (30) which are known to impact immune regulation, are
likely to impact immune competency and contribute to the risk
of genuine URTIs, rather than the acute and transient immune
changes that arise after the acute bout of exercise itself; these acute
immunological changes arising after acute exercise are discussed
later in this article (see Part A: “Is it Time to Close the Shutters on
the “Open-Window” Hypothesis? A Bout of Exercise Does Not
Suppress Immune Competency”; and see “Exercise and Salivary
IgA and Changes to Lymphocyte Frequency and Functional
Capacity in the Hours After Acute Exercise”).
Moreover, we contend that attendance at any mass participa-
tion event—whether it is a marathon or otherwise—is likely to
increase the risk of acquiring novel infectious pathogens, which
are in abundance due to the mass gathering of people. For exam-
ple, it has been shown that around 40% of individuals attending
the Hajj—a crowded religious event in Saudi Arabia—self-report
an URTI (31). In this study, there was a greater risk of infection
among those with the longest exposure to crowds (31). Thus, it
is important to consider that other underlying factors, often not
measured in the context of exercise and illness studies, likely
Frontiers in Immunology  |  www.frontiersin.org
Exercise, Health, and Immunity Across the Lifespan
play a greater role in infection risk than exercise participation
per se. For example, recently, it has been demonstrated that air
travel is a significant predictor of illness symptoms in athletes
(32). Infections linked to air travel are exacerbated by long-haul
flights crossing multiple time zones, implicating many other fac-
tors known to influence immune function, including exposure
to hypobaric hypoxia, radiation, temperature changes, sleep
disruption, fatigue, altered or inadequate diet, dehydration, and
psychological stress (32–34).
Contrary to the aforementioned reports that exercise height-
ens infection incidence, it is often overlooked that other studies
indicate that exercise participation may in fact reduce the inci-
dence of infections. For example, a recent prospective cohort
study of 1,509 Swedish men and women aged 20–60 years found
that higher physical activity levels were associated with a lower
incidence of self-reported URTIs (35). A much smaller but
very detailed analysis of illness records kept by 11 elite endur-
ance athletes over a period of 3–16 years showed that the total
number of training hours per year was inversely correlated with
sickness days reported (36). Similarly, another study of swim-
mers monitored for 4  years found that national level athletes
had higher incidence of infections than more elite international
level athletes (37). Finally, studies of ultramarathon runners,
who undertake the largest volume of exercise among athletes,
have shown that these individuals report fewer days missed
from school or work due to illness compared to the general
population. For example, the mean number of sickness days
reported over 12 months was 1.5 days in a study of 1,212 ultra-
marathon runners and 2.8 days in a study of 489 ultramarathon
runners (38, 39). These studies compared their findings to data
from the United States Department of Health and Human
Services report in 2009, showing that the general population
report on average 4.4 illness days each year. Thus, a number of
studies challenge the “J-shaped curve,” indicating that athletes
undertaking the largest training loads, become ill less frequently
than athletes competing at, and training at, a lower level. These
findings have previously been conceptualized by extending the
“J-shaped curve” into an “S-shaped curve,” thereby suggesting
that very elite athletes are better adapted to the demands of
their training (40). Given the nature of their design, very few
of these reports—akin to many of the aforementioned studies
showing increased infection risk among athletes following mass
participation endurance events—used appropriate laboratory
diagnostics to confirm an infection. However, despite their
limitations, it is important to highlight that there are as many
epidemiological studies showing that regular exercise reduces
infections as there are studies showing exercise increases infec-
tions, and that these studies are often overlooked in the exercise
immunology literature.
It should also be considered whether the commonly reported
“increased frequency” of illness symptoms among athletic
populations or those taking part in sporting events is indeed
more frequent than among the general population. For example,
large studies have reported that approximately 7–10% of athletes
competing in the Olympic Games report symptoms of illness
during the competition weeks (41, 42). However, accumulating
evidence suggests the incidence of infection among athletes is
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Campbell and Turner
not substantially different to other populations. For example, in
a telephone survey of 2011 adults considered to represent the
general population in the USA, 24% experienced a cold during
a 4-week period, which is a similar timeframe to many interna-
tional sporting competitions (43). In another telephone survey of
4,051 adults in the USA, 72% experienced at least 1 non-influenza
related URTI over 12  months, and on average, experienced 2
infections annually (44). In a year-long Internet-based monitor-
ing study of 627 individuals over 14  years of age in Germany,
weekly acute respiratory illness rates were 2.7–8.2%, manifesting
in 1.3–3.2 episodes annually (45). Thus, evidence suggests that the
frequency of illness episodes in athletic communities is similar to
the general population annually.
In the context of exercise participation in older age, it would
appear to be counterintuitive that the incidence of URTI symp-
toms appears to be inversely correlated with age: it has been
shown that URTI symptoms are more common in younger rather
than older runners (18). While, once more, this aforementioned
study did not confirm infections by laboratory analyses, it is
notable that if acute exercise does suppress immune compe-
tency, it might be expected that older adults—whom typically
have inferior immune function—would be at greatest risk of
exercise-induced immune suppression. Rather than exercise
per se, again, a more likely explanation for differences in illness
symptoms between groups of athletes are other factors present
before competing, such as fatigue, nutritional deficiency,
psychological stress, or environmental exposures. On the other
hand, proponents of the “open-window” hypothesis could
portend that experienced athletes have higher tolerance of the
symptoms associated with URTI, and/or have developed coping
methods or strategies to reduce symptoms. Alternatively, expe-
rienced athletes may have evolved strategies to reduce infec-
tion risk by adopting good practice (e.g., sleep, diet, hygiene)
before, during and following attendance at a mass participa­
tion event.
Separately, it has also been questioned whether illness
symptoms—even if confirmed to be infectious—are a result of
encountering a novel pathogen. For example, over a decade ago,
some studies suggested that reactivation of latent viruses—such as
Epstein Barr Virus which had most likely infected the host during
childhood—was responsible for illness symptoms after exercise
(46, 47). Although these studies suggest new pathogens were
not to blame, it was interpreted that exercise-induced immune
suppression had resulted in loss of viral control. However, herpes
viruses can reactivate even with a fully functioning immune
system, for example, in response to adrenergic activity, reactive
oxygen species and inflammatory cytokines (48–50), all of which
increase during exercise. Moreover, recent evidence appears
to discount herpes virus involvement in causing symptoms of
illness, by showing that individuals previously infected with
Cytomegalovirus, or those infected with both Epstein Barr Virus
and Cytomegalovirus, exhibited a lower incidence of illness symp-
toms than individuals not latently infected (51).
Taken together, evidence that participation in an acute bout of
vigorous exercise leads to heightened infection incidence remains
spurious. If symptoms of URTI are observed after a bout of vigor-
ous exercise, the cause is unlikely to be infectious. However, if
Frontiers in Immunology  |  www.frontiersin.org
Exercise, Health, and Immunity Across the Lifespan
infection or immune impairment is confirmed, their trigger is
more likely to be the physical, nutritional, and psychological
wellbeing of the individual prior to undertaking the single bout
of acute vigorous exercise. In the context of mass participation
sporting events, it is likely that increased exposure to pathogens,
or the influence of environmental factors that can affect immune
function (e.g., travel, sleep disruption) most likely explain genu-
ine infections. Thus, we conclude that it is unlikely that vigorous
and prolonged exercise heighten the risk of infections and should
not be considered a deterrent to those seeking to become more
physically active.
Exercise and Salivary IgA
A second mainstay of exercise immunology that has received
considerable attention over the last three decades is the assess-
ment of exercise-induced changes to mucosal immunity,
principally via measurement of IgA levels in saliva (52). Given
that IgA is the most abundant immunoglobulin in mucosal
secretions and that its principle role is the inhibition of invading
pathogens, isolated changes to salivary IgA following exercise
has been considered of some importance in light of the purport-
edly higher risk of infections among athletes (7, 8).
One of the earliest and most cited papers in this research area
found that IgA was reduced by 20% after 2–3 h of cross-country
skiing (53). Another study found that this effect is transient,
whereby salivary IgA concentrations decreased immediately
after 2 h of intensive cycling exercise, and remained low in sam-
ples collected 1  h post-exercise, but returned to normal levels
within 24  h (54). A criticism of these studies at that time was
that the absolute IgA levels reported did not adequately control
for the amount of saliva produced, and thus these results may
misrepresent IgA secretion. Although some studies measuring
IgA secretory rate (IgA protein concentration multiplied by
saliva flow rate) support the early findings with IgA concentra-
tion, others have shown profoundly contradictory results. For
example, in alignment with prior observations, it was found in
trained runners that IgA secretion rate decreased by 25% from
pre-marathon to 90 min post-marathon (55). Likewise, in a sepa-
rate study, a 20% reduction in IgA secretion rate was observed
in elite athletes after a 2-h rowing exercise session (56). Several
other studies of similar design reported analogous findings
(57–59); however, contradictory findings are also in abundance
but are much less cited in the literature. Indeed, an elegant study
exploring the effects of different exercise intensities, including
moderate- and high-intensity exercise to exhaustion, found that
although saliva flow rate decreased, IgA secretion rate actu-
ally increased in response to both of the exercise bouts. In the
words of the authors, exercise to exhaustion has an “effect on the
quantity of saliva, but not the quality of saliva” (60). Many other
studies have also reported that exercise does not elicit a decrease
in IgA secretion rates following exercise (61–66).
Any subtle isolated changes to IgA that occur after exercise
appear to be clinically insignificant as it would appear that the
increased incidence of URTI symptoms that has been purported
following vigorous and prolonged exercise is unrelated to salivary
immunoglobulin status. A longitudinal field study of participants
in the Comrades Marathon (86.5  km ultramarathon) in South
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Campbell and Turner
Africa found that salivary IgA levels in the 4 weeks prior to the race,
and 2 weeks following the race, were unrelated to the incidence of
self-reported URTI (67). In the aforementioned study, it was found
that symptoms of URTI were highest 4 weeks prior to the marathon,
and URTI symptoms seemed to re-appear within many of the same
athletes 1 or 2  weeks post-marathon. This study did not confirm
the re-emergence of infections by laboratory testing, but if this was
indeed demonstrated in future studies, it again shows that acute
exercise participation per se does not heighten risk of opportunistic
infections. In this case, an underlying infection, not resolved prior
to exercise participation, or some other idiosyncrasy, is perhaps to
blame. Such conclusions appear to be supported by evidence from
athletes who report the most frequent illness symptoms. For exam-
ple, these individuals exhibit mostly anti-inflammatory cytokine
responses when whole blood, collected at rest, is cultured ex vivo
with antigens from diphtheria, tetanus, acellular pertussis, poliomy-
elitis, and hemophilus influenza type b (68, 69). These findings sug-
gest the immune system may be functionally altered by underlying
illness, or is already different in these “illness-prone” athletes prior
to infection, rather than exercise affecting immune function per se.
A flaw in studies investigating the link between mucosal
immunity and purported exercise-induced infection risk is that
oral health status is rarely adequately evaluated. Salivary IgA is
heavily involved in host-bacterial ecology and mucosal homeo-
stasis (70, 71). As optimal oral health is rare in adults—with
nearly all exhibiting caries, gingivitis or periodontitis—pro-
found between-person IgA variation has been reported, which
is dependent on oral health status (71). Moreover, periodontal
diseases are complex and multifactorial, and as a result, studies
report large fluctuations in IgA levels relative to disease status
between persons, probably due to the bespoke ecological makeup
of different host mucosa (71). In addition, oral disease is a com-
mon problem in athlete populations (72), which is likely to be
caused by high volume and frequent carbohydrate consumption,
and in some, a neglect of oral hygiene, perhaps due to practical
constraints. Thus, changes to oral inflammatory status has not
been adequately considered, and emerging salivary biomarkers
of oral inflammation, such as immunoglobulin-free light chains
(73), may offer a means of controlling for this confounder. As
highlighted elsewhere (70), salivary IgA is also highly vulnerable
to short-term variation, in particular, due to circadian rhythms,
typically peaking in the morning, and falling thereafter (74).
As salivary IgA secretion is controlled by the parasympathetic
and sympathetic nervous system, psychological stress also plays
a powerful role in regulating IgA levels (75). Animal models
suggest that salivary IgA levels could vary up to 27-fold within
the same host over a short period of time (76). Salivary IgA
levels are also affected by factors such as sex differences (77),
diet, ethnicity, disease, medications, tobacco, and phase of
the menstrual cycle, as reviewed elsewhere (71). To overcome
some of these variations in salivary IgA, it is often the case that
studies evaluate only secretory IgA (sIgA; i.e., IgA containing
the secretory component) as this represents IgA produced by
local mucosal plasma cells, and not IgA from the bloodstream
transported via crevicular fluid. While this approach may
reduce some confounding error, most IgA in saliva contains the
secretory component and is, itself, subject to large variation;
Frontiers in Immunology  |  www.frontiersin.org
Exercise, Health, and Immunity Across the Lifespan
extensively reviewed elsewhere (78). Given these many consid-
erations, we propose that longitudinal measurement of salivary
IgA, as an isolated measure of immune competency within a
single host, and even more so between persons, depicts too
confusing a picture, and it is ambitious to say that any subtle
changes to salivary IgA following exercise reflects immune
suppression and a heightened risk of opportunistic infections.
Given the limitations of salivary IgA measurement, research is
being undertaken to explore mucosal IgA in other biofluids, and
a recent study has shown links between reduced tear IgA levels
and infection incidence (79). Others have moved toward more
comprehensive oral immunity panels (80), and such strategies
could benefit further from an integrative approach that, in addi-
tion to immune parameters, incorporates full dental examina-
tion, oral inflammation biomarkers, and host mucosal ecology.
Changes to Lymphocyte Frequency
and Functional Capacity in the Hours
After Acute Exercise
One of the most reproduced findings in human exercise physiol-
ogy is the profound and transient time-dependent change that
arises to the phenotypic composition and functional capacity
of lymphocytes in the peripheral bloodstream in response to
a single bout of exercise (8). During vigorous aerobic exercise,
it is commonly observed that peripheral blood lymphocyte
frequency—and, concomitantly, the functional capacity of the
lymphocyte pool—is dramatically increased, leading to the
concept that, during exercise, exercise appears to “stimulate”
the immune system. On the other hand, in the hours follow-
ing exercise, it is typically observed that total peripheral blood
lymphocyte frequency—and the functional capacity of the lym-
phocyte pool—is decreased below pre-exercise levels, leading
some to propose that exercise induces a short-term window of
immune suppression (termed the “open-window” hypothesis).
The purpose of this part of our review is to outline that it is
a misconception to state that the “reductions” to lymphocyte
frequency and function, that arise in the hours following acute
exercise, reflects immune suppression, and instead we emphasize
that during this post-exercise period, the immune system is in a
heightened state of immune surveillance and regulation.
Transient Changes to Blood Lymphocyte
Frequency in the Hours Following Exercise
The classic biphasic response of lymphocytes to acute steady
state vigorous exercise lasting for around at least 45–60 min-
utes, is first characterized by a dramatic lymphocytosis. This
response is typified by a dramatic influx of natural killer cells,
which rise by up to 10-fold, and CD8+ T cells which increase to
a lesser—but still profound—extent by approximately 2.5-fold
(81). This exercise intensity-dependent mobilization is driven
in part by increased shear forces and blood pressure during
exercise causing a non-specific flushing of the marginal pools
(82) but, moreover, is principally governed by adrenergic
stimulation of beta-2-adrenergic receptors on the surface of
lymphocytes, arising from adrenaline released during exercise,
causing endothelial detachment and subsequent recirculation
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Campbell and Turner
of lymphocytes into the bloodstream (83–85). Indeed, the
lymphocyte mobilization response observed during exercise
appears to broadly mirror the differential expression of beta-2
adrenergic receptors on lymphocytes: natural killer cells >
CD8+ T  cells  >  B  cells  >  CD4+ T  cells, including regulatory
T cells (81, 86–88). Upon exercise cessation, the classic biphasic
exercise response is next characterized by a dramatic decrease in
the frequency of lymphocytes in the bloodstream. This nadir is
typically observed approximately 1–2 h post-exercise when the
lymphocyte numerical count is lower than pre-exercise levels;
lymphocyte frequency normally returns to pre-exercise levels
within 24  h (87, 89, 90). The lymphopenia that occurs 1–2  h
later is exercise intensity dependent and the most profound
reductions during this period are typically observed among
natural killer cells and CD8+ T  cells (90). Akin to purported
reductions to salivary IgA, discussed earlier, it was perceived
that the numerical decline of blood lymphocytes that arises dur-
ing this time represented “double jeopardy” (89), temporarily
exposing an individual to impaired immune competency and
concomitantly providing an “open-window” for opportunistic
infections (91, 92).
Rather than suppressing immune competency however, a more
contemporary viewpoint is that this acute and transient lym­
phopenia 1–2 h after exercise is beneficial to immune surveillance
and regulation. Indeed, in what appears to be a highly specialized
and systematic response, it is widely proposed that exercise rede-
ploys immune cells to peripheral tissues (e.g., mucosal surfaces)
to conduct immune surveillance. Here, these immune cells are
thought to identify and eradicate other cells infected with patho-
gens, or those that have become damaged or malignant, termed
the acute stress/exercise immune-enhancement hypothesis (93).
A seminal study by Kruger and colleagues, using fluorescent cell
tracking in rodents, found that T  cells are redeployed in large
numbers to peripheral tissues including the gut and lungs, and
to the bone marrow following exercise (84, 94). In line with
Dhabhar’s theory, it is hypothesized that this redistribution
reflects heightened immune surveillance in sites where patho-
gens are likely to be encountered during and after exercise (i.e.,
lungs, gut). This response has also been proposed to maintain
immune homeostasis via augmented regulatory activities (12).
In this context, evidence implies that bone marrow homing and
subsequent apoptosis of senescent T cells stimulates the produc-
tion or mobilization of new progenitor cells into the periphery
(95), which has been hypothesized as an exercise-induced means
of maintaining a younger immune system (12), discussed later
in Part C “Does Exercise and Regular Physical Activity Influence
Immunological Ageing.” Links between exercise-induced
apoptosis and lymphopenia have in the past been interpreted as
detrimental, with speculation that apoptosis could be responsible
for the fall in lymphocyte number in the hours after exercise (96,
97). Other studies have reported increased lymphocyte apoptosis
immediately after exercise (i.e., as a result of the large mobili-
zation of cells) but not in the hours following exercise during
lymphopenia (98–100). Although the magnitude of lymphocyte
apoptosis reported in studies is dependent on the measurement
technique, typically <10% of lymphocytes undergo post-exercise
apoptosis (96, 97). Given the 30–60% decrease in lymphocyte
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Exercise, Health, and Immunity Across the Lifespan
numbers post-exercise (89, 101, 102), apoptosis could be a small
contributor to exercise-induced lymphopenia, but this process
of cell death is likely to be beneficial given the stimulation of
progenitor cells from the bone marrow (95).
While it has not been shown in humans that exercise—in
line with rodent models—causes the redistribution of immune
cells to peripheral tissues, further support for a coordinated,
exercise-induced immune surveillance response elicited
by lymphopenia, is revealed by studying the phenotypic
charac­teristics of the cells that preferentially mobilize and
subsequently extravasate out of the circulation after exercise.
With regard to natural killer cells—the most exercise-
responsive lymphocyte subset—CD56dim cells are preferen-
tially redeployed rather than their CD56bright counterparts
(81). CD56dim cells are a mature subset of natural killer cells
which have exclusive migratory potential for non-lymphoid
tissue and potent effector capabilities, including the capacity
to produce high amounts of perforin and granzyme, whereas
CD56bright cells are a more immature regulatory cell subset
(103) and reside in secondary lymphoid organs, typified
by their cell-surface expression of CD62L and CCR7 (104).
CD56dim natural killer cells can be further dissected, into cells
with highly potent effector function based on loss of NKG2A
and expression of killer immunoglobulin-like receptors and
CD57 (105, 106). In a recent study, it was shown that these
natural killer cells, which are capable of rapid effector func-
tions, are preferentially redistributed after exercise (107, 108).
Synergistically, T cells also appear to exert heterogeneous but
highly coordinated responses to acute exercise. Indeed, it is
consistently observed that discrete populations of CD8+ but
not CD4+ T cell subsets are redeployed by exercise. For some
time, there was confusion pertaining to the exact behavior
of CD8+ T  cells in response to exercise. Rather than losing
or gaining markers of adhesion or activation—as evaluated
elsewhere (8)—these changes represent a uniform redeploy-
ment of a preferentially mobilized group of memory cells. In a
flurry of studies about a decade ago, it was shown that exercise
selectively mobilizes memory CD8+ T cells with a phenotypic
propensity for homing to peripheral tissues—typified for
example by CD11, and not CCR7 or CD62L expression—and
the distinctive capacity to mount rapid effector functions (81,
109–111). This response presumably facilitates the detection
and elimination of neoplastic, stressed or infected cells in
synergy with natural killer cells, as proposed elsewhere (112).
Aligned with the immune surveillance theory of Burnet
and Thomas, reviewed elsewhere (113), these results imply
that sentinel cells of the immune system are redeployed by
exercise-induced perturbations to stress hormones, to exert
effector functions against neoplastic, stressed, or infected cells
in the hours following exercise. This process, which occurs
daily in a natural diurnal process (114), orchestrated subtly by
stress hormones (115, 116), appears to be primed in response
to exercise, leading to enhanced immune surveillance (117).
Principles of the acute stress/exercise immune-enhancement
hypothesis continue to be investigated. For example, it has
recently been shown that acute exercise does not preferentially
mobilize CD8+ T cells and natural killer cells with the capacity
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Campbell and Turner
for skin-homing (118). However, skin-homing in this context
is a role that may be fulfilled by exercise-responsive mucosal-
associated invariant T cells (119); but further work is needed
in this area.
A key example illustrating how exercise-induced immune
cell redistribution is beneficial to host health can be found in
the rapidly emerging field of exercise oncology. Indeed, a recent
seminal study demonstrated inhibition of tumor onset and dis-
ease progression across a range of tumor models in voluntarily
active rodents (112). In this work, natural killer cell infiltration
was significantly increased in tumors from active versus inactive
rodents, leading to the conclusion that the presence of natural
killer cells (but perhaps also T cells) in tumor sites, redeployed
by adrenaline during exercise stress, “provides a spark” for
tumor elimination, in what could be considered a form of
“exercise immunotherapy” (112, 120). Importantly, administra-
tion of propranolol—a beta 2 adrenergic blocker—abolished
the adrenaline-induced redistribution of immune cells, and
nullified the anti-tumor effect of exercise on neoplastic growth
(112). While these studies are limited to rodents, there is grow-
ing evidence that exercise may promote anti-cancer effects in
humans. For example, in a key study recently conducted in
humans, it was shown that natural killer cells with a highly
mature effector phenotype are preferentially redistributed after
exercise, and have the capacity to exert augmented cytotoxicity
against myeloma and lymphoma cells in vitro (107, 108). In light
of these results, research is now being conducted to harness the
beneficial impact of acute exercise on lymphocyte kinetics for
the purposes of cancer immunotherapy (121). It is beyond the
scope of this review to discuss other findings in this exciting field
and we briefly conclude that the aforementioned studies imply
that exercise-induced lymphocytosis, and the lymphopenia that
follows, is beneficial to the immune system’s capacity to iden-
tify and neutralize damaged and neoplastic cells in peripheral
tissues. Furthermore, in the context of neoplastic growth, this
process may be directly responsible for reduced incidence of
cancer among physically active people across the lifespan (122).
Further comprehensive discussion of the role of exercise and
lymphocyte kinetics in anti-tumor responses can be found else-
where (117). Clearly more research is needed in this area, and
a shift in focus toward investigating the benefits—rather than
purported detrimental effects—of exercise on health, is no doubt
underway and will be a key focus for exercise immunologists in
the coming years.
Transient Changes to Blood Lymphocyte
Function in the Hours Following Exercise
A common misinterpretation, brought about by the exercise-
induced reductions to blood lymphocyte frequency in the hours
following exercise, is the observation that the functional capacity
of immune cells in the peripheral blood is reduced in the hours
following vigorous exercise. As measurements of cell function
in peripheral blood are entirely dependent on the cells present
at the time of sampling, a change to the composition of the cells
in blood in the hours after exercise—as outlined in the section;
“Transient Changes to Blood Lymphocyte Frequency in the
Hours Following Exercise”—will consequently lead to parallel
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Exercise, Health, and Immunity Across the Lifespan
changes in overall cell function, indicated by the performance
of the sampled cells being assayed. For example, among CD8+
T cells, subsets that exhibit strong effector function (e.g., CD45
RA+CD27−CD28−CCR7−CD62L−CD57+), substantially increase
during exercise (81, 123). Thus, during exercise, blood is pre-
dominantly occupied by cells capable of responding strongly
(i.e., IFN-gamma production) to in vitro stimuli, and therefore,
many studies have shown an increase in IFN-gamma production
by cells isolated close to the exercise stimulus. In the hours fol-
lowing exercise, the same effector CD8+ T cells are subsequently
redeployed to peripheral tissues, and, as such, this results in
the blood having fewer cells capable of responding strongly
to in  vitro stimuli, thus explaining the commonly reported
decrease in cellular function post-exercise. These effects have
been neatly demonstrated approximately two decades ago when
it was shown that IFN-gamma production by stimulated CD8+
T cells is reduced 2 h after completing a prolonged 2.5 h bout
of cycling (124). Importantly, it was shown that this reduced
capacity to produce IFN-gamma was due to a reduced number
of IFN-gamma-positive CD8+ T cells in peripheral blood at the
same time-point (124, 125).
The same principles apply to other cell functions, such as
in vitro proliferation in response to mitogenic stimuli. However,
with this measurement in particular, the commonly reported
increase in T cell proliferation immediately after acute bouts of
exercise is also strongly influenced by laboratory processes and
in  vitro assay conditions (e.g., blood processing, temperature,
mitogen selection) (126). A recent meta-analysis of 24 studies
concluded that lymphocyte proliferation is suppressed following
acute bouts of exercise, and that a greater magnitude of sup-
pression is caused by exercise lasting longer than 1 h, regardless
of exercise intensity (127). However, this meta-analysis did
not examine the most important determinant of cell function
following exercise: the time-dependent changes in the cellular
composition of the samples assayed. Thus, findings such as these
should be interpreted with caution if analyses did not differentiate
between studies collecting samples immediately after exercise or
in the hours following.
As with research focusing on T cells, a similar group of stud-
ies citing reductions to natural killer cell cytotoxicity following
acute exercise, reviewed elsewhere (128), did not always take into
account dramatic shifts in the constitutional makeup of the natu-
ral killer cell compartment, which is known to change in response
to exercise (81). Once more, changes to the functional capacity of
the total natural killer cell pool are likely to have been misrepre-
sented, given that many of these cells, with potent effector func-
tions, are redistributed to peripheral tissues following exercise
cessation. The principles discussed herein regarding lymphocyte
function are also broadly applicable to the assessment of function
in other cells, such as neutrophils and monocytes; the response
of these cells to exercise is beyond the scope of this article and is
reviewed elsewhere (8).
Taken together, it is important to emphasize that statements
such as “acute intensive exercise elicits a depression of several
aspects of acquired immune function” and “prolonged bouts of
heavy exertion reduce the normal functioning of all major immune
cell subtypes” mentioned elsewhere (8, 15) should be interpreted
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Campbell and Turner
with caution. We conclude that the results of studies exploring
the effects of acute exercise on cell function must be considered
very carefully in light of the time-dependent changes in the
cellular composition of blood that typically arise following a
vigorous bout.
Summary: Exercise Induces Lymphocyte
Immune Surveillance Not Immune Suppression
In summary, strong evidence implies that a reduction in the
frequency and function of lymphocytes (and other immune
cells) in peripheral blood in the hours following vigorous
and prolonged exercise does not reflect immune suppression.
Instead, the observed lymphopenia represents a heightened
state of immune surveillance and immune regulation driven by
a preferential mobilization of cells to peripheral tissues. As such,
nutritional interventions, which have been employed to dampen
the magnitude of exercise lymphopenia (124, 129) are unlikely
to reduce the incidence of infections, but inter­ventions that
augment exercise-induced lymphocyte trafficking may provide
benefits (130).
PART B: REGULAR PHYSICAL ACTIVITY
AND FREQUENT EXERCISE AUGMENT
ASPECTS OF IMMUNE COMPETENCY
ACROSS THE LIFESPAN
Contrary to a commonly held belief—outlined in Part A “Is it
Time to Close the Shutters on the “Open Window” Hypothesis?
A Bout of Exercise Does Not Suppress Immune Competency?”—
that acute vigorous exercise can suppress aspects of immune
function, an increasingly large body of research indicates
that both single bouts of exercise, or frequent participation
in regular exercise, can act as an adjuvant to stimulate the
immune system. Numerous methods exist to assess the effects
of behavioral interventions on immunity (131) but arguably
the optimal means of evaluating global immune competency
at a systems level is via assessment of the immune response to
in vivo challenge, ideally with a novel and clinically recognized
pathogen, for example via vaccination (132). Thus, here, in the
first section of Part B “Regular Physical Activity and Frequent
Exercise Augment Aspects of Immune Competency Across the
Lifespan,” we focus on the influence that exercise has on immune
responses to antigenic challenge, which requires a coordinated
response from most, if not all, innate and adaptive immune
system components. In light of the age-associated decline in
immune competence with aging—caused in part by underlying
changes to the numerical, phenotypic, and functional capacity
of almost all innate and adaptive immune cells—the second sec-
tion of Part B “Regular Physical Activity and Frequent Exercise
Augment Aspects of Immune Competency Across the Lifespan,”
will evaluate the impact aging has on the immune benefits that
can be attained from exercise throughout the lifespan. A detailed
discussion of immunological aging processes and the influence
that an active lifestyle has on established biomarkers of an
aging immune system is covered in Part C “Does exercise and
Regular Physical Activity Influence Immunological Ageing?” of
this article.
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Exercise, Health, and Immunity Across the Lifespan
Exercise and Immune Responses
to Experimental In Vivo Challenge
Across the Lifespan
In a research context, the most clinically relevant model to
assess in  vivo challenge in a controlled manner is via vaccina-
tion. Vaccine administration assesses the integrated capacity of
the immune system to recognize and process antigen, leading to
antigen neutralization. In a clinical research context, vaccination
responses are principally quantified clinically in two ways, either
via antibody production from antigen-specific plasma cells or via
cytokine responses—typically IFN-gamma production—from
T cells stimulated with cognate antigen.
Vaccination: Effects of a Single Exercise Bout
Evidence from an array of studies, evaluated recently in a com-
prehensive review elsewhere (9), indicates that a single acute bout
of exercise appears to enhance immune responses to vaccination
in both younger and older individuals. The majority of studies
to date have examined muscle-damaging upper arm resistance
exercise performed close to the time of vaccination which is
administered shortly after the regimen into exercised muscle.
However, other modes of exercise, including acute bouts of whole
body aerobic activity, have also been investigated. Six of the eight
trials identified in the aforementioned review indicated a sta-
tistically significant exercise-induced enhancement of immune
responses against constituent antigens contained within the
vaccine administered (133–138). It is notable that in five of these
studies, statistically significant benefits were found where the
vaccine strains appeared to have lower immunogenicity (9). For
example, it was shown in a trial of 133 young adults, approximately
20 years of age, receiving either a full- or half-dose Pneumovax-23
(a pneumococcal vaccine), that those who exercised at the time
of receiving the half-dose vaccine had heightened responses to
five of the eleven pneumococcal strains contained in the vaccine,
whereas no differences were observed for the other six strains;
and no benefits of exercise were observed for the full-dose vac-
cine (137). As such, given the potential effectiveness of exercise
as an adjuvant in  situations where vaccine immunogenicity is
low, studying the effects of exercise on antibody responses in
older adults—whom typically exhibit impaired responses—has
received considerable attention. In one recent study, it was found
that antibody responses in women 55–75  years of age, were
significantly improved when moderate-intensity aerobic exercise
was performed immediately prior to vaccination; however, no
beneficial effects were found in men (138). Another trial reported
no benefits of a single 45-min bout of moderate-intensity walking
exercise on the immune response to influenza and pneumococ-
cal vaccination in women around 47 years of age (139). Finally,
a very recent study found no effect of a bout of resistance exer-
cise on antibody responses to influenza vaccination in adults
approximately 73 years of age (140). It is possible that a number
of factors including immunological aging, biological sex and
variations in sex hormone levels, and perhaps latent infections
(e.g., herpes viruses) (141–143) limit the immunostimulatory
effects of exercise, and many studies have not adequately con-
trolled for these factors. Alternatively, in light of the mechanisms
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Campbell and Turner
proposed in the acute stress/exercise immune-enhancement
hypothesis (93), it is plausible that more intensive exercise may
be needed to elicit enhanced vaccine responses. Despite null
findings, it is important to point out that few, if any, studies inves­
tigating the effects of acute exercise on vaccination responses
have reported exercise-induced impairment to immune respon­
ses, and rather, these studies report that exercise has no effect,
or in some cases a beneficial effect, on the immune response to
vaccination in older adults.
Vaccination: Effects of Frequent Exercise Bouts
Data from vaccine studies exploring the effects of regular physical
activity or frequent exercise training on the immune response to
vaccination provides robust support for the argument that exercise
enhances, rather than suppresses immunity. Indeed, at least eight
studies have demonstrated heightened vaccination responses
in older adults, typically over 60 years of age, who are physically
active (144–151). For example, an early study categorized adults
aged 62 years or older, into one of three groups: active (undertak-
ing at least 20 min of vigorous exercise three or more times per
week), moderately active (undertaking regular exercise but with
lower intensity, frequency, and/or duration), or sedentary (non-
exercisers). Two weeks after influenza vaccination, it was shown
that serum anti-influenza IgG and IgM titers were higher in
active versus sedentary adults, and so too were peripheral blood
mononuclear cell responses to antigen-specific stimulation (144).
In addition, a recent study has shown that men aged 65–85 years,
who regularly undertook moderate or vigorous exercise training,
exhibited higher antibody responses compared to inactive controls
in response to an influenza vaccine (151). Data linking habitual
levels of physical activity to enhanced immune competency in
humans are supported by evidence from animal studies, and
show that the immunological benefits of exercise may be particu-
larly beneficial in enhancing otherwise poor responses in older
age (152).
Interpreting Data From Vaccine Trials
A major criticism of vaccine and exercise trials conducted in
humans is that many solely focus on the maximal antibody titer
following vaccination, and it is not practical to follow-up with
investigations into infection incidence as a gauge of protection
status following vaccination (153). As such, it is unknown
whether differences observed with absolute antibody titers, or
the amount of IFN-gamma produced from stimulated T  cells,
between exercise and control groups, is representative of clini-
cally meaningful benefits in terms of protection from infections.
Three elegant studies in rodents imply that benefits, beyond
antibody titer, may be brought about by acute exercise. In one of
these studies, it was found that antibody responses to influenza
exposure were lower in rodents that exercised around the time of
exposure, compared to those that did not exercise, yet, exercised
mice were still protected and did not exhibit any signs of infec-
tion upon re-exposure to the virus (154). Moreover, in an earlier
study by the same authors, it was found that mice undertaking an
acute bout of exercise before being expose to influenza exhibited
a lower severity of infection and had enhanced viral clearance
and lower inflammation in the lungs in the days following
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Exercise, Health, and Immunity Across the Lifespan
(155). Thus, it may be the case that exercise enhances immune
responses, beyond those captured using maximal antibody titer
as an endpoint. In accordance with this view, an elegant rodent
study conducted by an independent group (156) found that mice
exercised for 20–30 min at moderate intensity 4 h after intrana­
sal influenza exposure had a substantially higher survival rate
(18 of 22 survived; 82%) when compared to mice that did not
exercise after influenza exposure (10 of 23 survived; 43%).
Contact Sensitivity Reactions and Acute
Exercise Bouts
More recent studies have examined the effects of acute exercise
on immune competency using other in  vivo models of immune
challenge that, in principle, also assess the coordinated efforts of
immune system components. These studies have employed con-
tact-sensitivity reactions by topically applying to skin, the dendritic
cell and T  cell stimulant (or attractant) diphenylcyclopropenone
(DPCP), and the non-specific inflammatory stimulant, croton oil
(157, 158). For example, in studies of young adults (approximately
20–30 years of age), by applying a primary sensitizing dose of DPCP
20  min after 2  h of moderate-intensity treadmill running, and
assessing recall challenge 4 weeks later, it has been concluded that
this form of exercise impairs both the induction of T cell immunity
and the memory response (159, 160). Thirty minutes of moder-
ate- or vigorous-intensity running had no effect, and no forms
of exercise modulated the non-specific inflammatory challenge
in response to croton oil (159, 160). Although these findings are
biologically interesting, the clinical relevance of exercise-induced
change is unclear, in part, because the process of DPCP-induced
immune modulation is not well defined (158) unlike the immune
response to antigen administration by vaccination.
Summary: Exercise Enhances Immune Responses
to In Vivo Antigenic Challenge
We conclude that there is growing evidence from a powerful
array of studies in humans and rodents, indicating that exercise
enhances, or at least does not suppress immune responses
to in  vivo challenge in younger and older individuals. These
observations—which contradict those predicated by the “open-
window” hypothesis—support the contention that an acute bout
of exercise has no detrimental immune consequences for health.
Thus, exercise should be encouraged, particularly for older adults
who are at greatest risk of infections and who may obtain the
greatest exercise-induced benefits to immune competency; an
overview of the impact of aging on the immunological benefits
that can be attained from exercise is described next.
Does Aging Influence the Immunological
Benefits of Exercise and Regular Physical
Activity?
Effect of a Single Exercise Bout
Research investigating the effects of exercise on immune
function has sought to establish whether the observed ben-
efits, as outlined earlier in young adults, such as exercise-induced
immune cell mobilisation, that has been implicated in protection
against cancer, is also applicable to older adults. For example, it
has been reported that the magnitude of T  cell mobilization
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Campbell and Turner
in response to acute vigorous exercise is smaller in older
(65 ± 1 years) compared to younger (22 ± 1 years) adults (161,
162). However, in this study, it was also shown that following
exercise, the magnitude of T  cell proliferation in response to
mitogens was smaller in young adults, whereas a similar exercise-
induced stimulation of natural killer cell cytotoxicity was obser­
ved for both groups (161, 162). It is beyond the scope of this
review to fully critique investigations examining the influence of
single exercise bouts on the function of different immune cells,
with comparisons made between younger and older individuals
across the lifespan; we refer the reader to comprehensive reviews
on this topic (163–165). Nevertheless, it is important to point
out that many studies in this area are difficult to interpret: at the
time of their publication, the influence of Cytomegalovirus infec-
tion on the magnitude of exercise-induced immune responses
was not known and was therefore not considered (123, 166).
Moreover, while the magnitude of change to lymphocyte kinet-
ics is likely to be important for detecting and eliminating viral
and bacterial infections and neoplastic cells, this process is
complex to study, and comparisons between younger and older
people is difficult, partly due to other age-associated changes
that influence the physiological response to exercise, such as
the decline in fitness (e.g., sarcopenia, cardiorespiratory fitness)
with age. It is likely that some, or all of these factors impact
upon on the efficacy of exercise as an adjuvant to vaccination
responses in older adults, outlined earlier in the section “Exercise
and Immune Responses to Experimental In  Vivo Challenge
Across the Lifespan.” In light of the challenge interpreting the
clinical relevance of the aforementioned lymphocyte kinetics
studies, from here onward, we briefly evaluate the impact of
regular physical activity or frequent exercise bouts on immune
competency across the lifespan, using measurements in samples
collected from participants at rest.
Frequent Bouts of Exercise
Immune competency at rest has been assessed in cross-sectional
studies, comparing elderly individuals differentiated by physi-
cal activity level or cardiorespiratory fitness, or by examining
immune function before and after structured exercise training
interventions. For example, it has commonly been reported
among the elderly, that the most active participants, compared to
those who are least active, show the highest T cell proliferation and
cytokine production in response to mitogens (163–165). Fewer
studies have assessed innate immune competency, but higher
natural killer cell cytotoxicity has been consistently shown among
the elderly who are active compared to less active age-matched
controls (163–165). Recent studies have expanded measurements
into other innate immune cells such as neutrophils. For example,
a recent cross-sectional study of 211 elderly adults, showed that
neutrophils from the 20 most active participants, compared to the
20 least active participants, migrated toward interleukin (IL)-8
with greater chemotactic accuracy, but there were no differences
in chemotactic speed (167). In addition, a recent exercise train-
ing study has shown in both young and middle-aged adults, that
10  weeks of moderate-intensity continuous cycling training,
or high-intensity interval cycling training, improve neutrophil
and monocyte phagocytosis and oxidative burst irrespective
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Exercise, Health, and Immunity Across the Lifespan
of age (168). Improvements in these common measurements
of immune competency, however, are not always consistent in
longitudinal studies employing exercise training interventions,
with around half of studies reporting improvements, and half
reporting no change (163–165). One reason for this could be
because the dramatic effects of Cytomegalovirus on driving
immunological aging was not considered by most of these studies,
and it is feasible that results would be different when examining
individuals who are latently infected compared to those who are
seronegative. Importantly however, no studies report impaired
immune competency from increased participation in structured
exercise. Altogether, we conclude that despite declines in fitness
and immune competency, aging does not appear to negate the
immunological benefits that can be attained from exercise, and
indeed, frequent participation in exercise across the lifespan may
lead to immune benefits, even in older age.
PART C: DOES EXERCISE AND REGULAR
PHYSICAL ACTIVITY INFLUENCE
IMMUNOLOGICAL AGEING?
Since the first exercise immunology research in the early 1900s,
and the substantial increase in scientific interest from the late
1980s and early 1990s (169), studies examining interaction
between immune function and lifestyle factors such as exercise and
physical activity have become common. Although a few exercise
studies published in the last 10–15 years have investigated some
immunological processes relevant to aging, health, and disease,
the theme of exercise-induced “immune suppression” continues
to influence the design of new studies or at least features in the
interpretation of findings and is often justified or contextualized
with relevance to self-reported illness symptoms among athletes.
As outlined in Part A “Is it Time to Close the Shutters on the
“Open-Window” Hypothesis? A Bout of Exercise Does Not
Suppress Immune Competency,” there is limited reliable evidence
to show that exercise heightens risk of opportunistic infections,
but there is, however, a growing body of evidence to show that
exercise enhances, rather than suppresses, immune competency,
as summarized in Part B: “Regular Physical Activity and Frequent
Exercise Augment Aspects of Immune Competency Across the
Lifespan.” The beneficial effects of exercise on immune function
are likely to be greatest for elderly people exhibiting the age-
associated deterioration of immune competency, also referred
to as immunosenescence. Moreover, preliminary evidence sug-
gests that physical activity and regular structured exercise may
even limit or delay immunological aging. Here, in Part C: “Does
Exercise and Regular Physical Activity Influence Immunological
Ageing?” we evaluate whether an active lifestyle influences
immunosenescence.
The Aging Immune System
Aging is associated with profound changes to the numerical, phe-
notypic, and functional capacity of almost all innate and adaptive
immune cells, resulting in altered immune responses. Some innate
immune cells exhibit numerical, phenotypic, and functional altera-
tions with aging, whereas others appear to be less affected (170).
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For example, the numbers and functions of eosinophils, basophils,
and mast cells appear to be largely unchanged with aging, or at
least, there is not a clear effect of age based on the limited current
literature (170). Neutrophil numbers often increase with aging, but
these cells exhibit diminished phagocytosis and impaired chemo-
taxis, although chemokinesis is maintained (170). Natural killer
cells increase with aging, driven by an accumulation of cytotoxic
CD56dim cells but a decline in regulatory CD56bright cells, and over-
all, cytokine production and cytotoxicity are less on a per cell basis
(170). Other innate lymphocytes, such as invariant CD1d-restricted
natural killer T cells (iNKT cells), which represent <1% of the T cell
pool, decline in number but age-associated changes to their func-
tion have not been established (171). Monocyte numbers are stable
with aging, but classical cells (CD14++CD16−) decline, and inter-
mediate (CD14+CD16+) and non-classical (CD14+CD16++) cells
increase, but overall, monocyte cytokine production is impaired
(170, 172). These changes with blood monocytes are thought to
be mirrored by tissue-resident macrophages, whereby classically
activated M1 cells decline, and alternatively activated M2 cells
accumulate (173). However, alterations in tissue-resident cells with
advancing age are very likely to be a result of adipose tissue accu-
mulation and dysfunction that also occurs in parallel with aging
(174, 175). Indeed, inflamed adipose tissue attracts macrophages
with cell-surface characteristics similar to M2 alternatively activated
cells—often assumed to be anti-inflammatory. However, despite
their cell-surface phenotype, these cells are potent producers of
inflammatory cytokines in adipose tissue, and likely drive age- and
obesity-associated inflammation (176–179). Thus, the M1/M2
paradigm for macrophages is likely to be an over-simplification
(180, 181). It is unknown if other, primarily tissue-resident cells,
are affected by adipose tissue dysfunction, but with aging, the
number and function of dendritic cells have been reported to
decrease in the skin and mucosal membranes (170). There is also
an age-associated increase in myeloid-derived suppressor cells—a
heterogeneous population of granulocytes, macrophages, and
dendritic cells—that may impair aspects of immune function by
producing reactive oxygen species and inhibitory cytokines (182).
Within the adaptive immune system, there are substantial
changes to the numbers, function, and phenotype of T cells with
aging. Among the broad population of CD4+ T-helper cells, aging
is associated with a predominance of Th2 (i.e., IL-4 and IL-10),
and Th17-producing cells (i.e., IL-17-producing cells that are
associated with autoimmune disease), whereas there is a decline
in cells with a Th1 profile [i.e., IFN-gamma- and tumor necrosis
factor-alpha (TNF-alpha)-producing cells] (183, 184). With
aging, the numbers and proportions of antigen-inexperienced
CD4+ and CD8+ T cells decreases (e.g., CD27+CD28+CD45RA+
CD57−CD62L+CCR7+KLRG1− naïve cells) (185, 186). In parallel,
the numbers and proportions of antigen-experienced CD4+ and
CD8+ T  cells increases (e.g., CD27−CD28−CD45RA+CD57+CD
62L−CCR7−KLRG1+ memory cells), and these cells are potent
producers of inflammatory cytokines (185, 186). These changes
are driven by lower hematopoietic stem cell numbers, thymic
involution resulting in reduced output of antigen-naïve T cells,
and infection with latent viruses, in particular Cytomegalovirus
(185, 187). With aging, T  cells that express natural killer cell-
associated cell-surface proteins (NKT-like cells) also accumulate,
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Exercise, Health, and Immunity Across the Lifespan
exhibiting similar changes to their phenotype, functional proper-
ties, and specificities as with the broader population of CD4+ and
CD8+ T cells (171). There is an age-associated decline in the total
number of γδ T cells; however age per se, in the absence of chronic
infections, is associated with a decline in Vδ2 cells (60–80% of γδ
T cells), whereas Vδ1 (15–20% γδ T cells) remain stable (188).
Some evidence suggests that γδ T  cell proliferative responses
are impaired with aging, perhaps due to increased susceptibility
of Vδ2 cells to apoptosis (189, 190). Natural regulatory T  cells
increase with aging whereas inducible regulatory T cells decrease,
but it is unclear if their function is affected (191). As with T cells,
aging is associated with a decline in the numbers and proportions
of naïve B cells, an accumulation of memory B cells with limited
specificities, and impaired plasma cell antibody production (192).
Several robust and accepted hallmarks of immunosenescence
have been established, especially within the adaptive immune
system. For example, low numbers and proportions of naïve
T  cells (in particular CD8+ T  cells) and high numbers and
proportions of memory T cells (especially late-stage differenti-
ated CD8+ T  cells) are well established biomarkers (185, 186,
193, 194). In addition, a cluster of parameters, revealed in
longitudinal studies of octogenarians and nonagenarians from
an isolated population in Sweden, have been referred to as the
immune risk profile (195–197). Biomarkers included low num-
bers and proportions of B cells, high numbers and proportions
of late-stage differentiated CD8+ T  cells (i.e., CD27−CD28−),
poor T  cell proliferation in response to mitogens, a CD4:CD8
ratio of <1.0, infection with Cytomegalovirus and high plasma
IL-6, which together, predicted greater all-cause mortality at
2-, 4-, and 6-year follow-up (195, 197–200). Indeed, the age-
associated increase in systemic inflammation, referred to as
“inflammageing” is another principle observation among aging
and longevity studies (201, 202). Subsequently, high levels of
IL-6, TNF-alpha, and C-reactive protein, have been associated
with shorter survival (203–205). Overall, it is well established
that elderly individuals exhibit impaired immune responses to
in vivo challenge with novel antigens (143, 206, 207) and these
individuals are subsequently thought to be at increased risk of
infection. Encouragingly however, as outlined in Part B: “Regular
Physical Activity and Frequent Exercise Augment Aspects of
Immune Competency Across the Lifespan” exercise can be a
potent stimulus of immune function, including the response
to vaccination, and some evidence suggests that exercise might
delay or limit the age-associated decline in immune competency.
Relationships Between Exercise and
Regular Physical Activity With Hallmarks
of an Aging Adaptive Immune System
As summarized in Part B: “Regular Physical Activity and Frequent
Exercise Augment Aspects of Immune Competency Across the
Lifespan” many studies have examined the influence of regular
physical activity or frequent structured exercise on the function
of the adaptive immune system with aging (163–165). Here, we
focus on recent studies that have examined relationships between
exercise, physical activity or cardiorespiratory fitness, and the
numbers and proportions of CD4+ and CD8+ naïve and memory
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Campbell and Turner
T  cells, as hallmarks of immunosenescence. Indeed, a small
number of studies have investigated whether the characteristics
of the T cell pool are influenced by an active lifestyle. There is a
larger body of evidence in young adults, typically between 18 and
30 years, compared to older adults, hereafter considered as being
over 40 years of age due to the characteristics of studies published to
date. If an active lifestyle can be linked with a smaller accumulation
of memory T cells, and a smaller decline in naïve T cells, then in
young adults, one interpretation might be that exercise prevents, or
at least delays immunosenescence, whereas in older adults, these
associations could be interpreted as countering or limiting the
development of an age-associated immune profile.
Experimental Evidence in Young People: Can
Exercise Prevent or Delay Aging of the Adaptive
Immune System?
The characteristics of the T  cell pool have been examined in
16 young adults (50% male; 18  ±  2  years) classified as being
very active (well-trained soccer players self-reporting 9–12  h
of exercise per week) and compared to 16 young adults (50%
male; 19  ±  2  years) classified as being untrained (individuals
self-reporting 2–3 h of exercise per week). Untrained individu-
als showed the highest proportions of CD4+ and CD8+ memory
T cells, and the lowest proportions of CD8+ naïve T cells, defined
on the basis of CD57 and CD28 expression (208). Although these
results suggest that regular exercise might limit the age-associated
accumulation of memory T cells and decline in naïve T cells, the
effects were strongly influenced by sex: only untrained males
exhibited high proportions of memory T cells and low propor-
tions of naïve cells compared to trained males, and these effects
were driven by changes in the CD4+ T cell pool (208). Extending
these findings by examining a female-only population of young
adults, the same authors compared 13 well-trained soccer players
(self-reporting around 12 h of exercise per week; 20 ± 2 years) to
13 untrained controls (self-reporting around 3 h of exercise per
week; 21  ±  2  years) (209). Trained females exhibited a greater
proportion of CD8+ naïve T cells compared to untrained females,
but these associations did not remain statistically significant after
controlling for body fat percentage (trained 21.7  ±  4.0 versus
untrained 25.1 ± 4.1%, p < 0.05) (209). Indeed, very few studies
have considered whether relationships between an active lifestyle
and markers of an aging immune system could be influenced by
other factors, such as body composition. Recently, a very small
study of 15 males aged 30  ±  4  years, categorized participants
using a combination of gold standard methods for measuring
physiological and lifestyle variables (210). Three groups were
formed (sedentary, active, and very active) on the basis of
objectively assessed habitual physical activity, directly measured
cardiorespiratory fitness, and body composition assessed with
dual energy X-ray absorptiometry (210). This work showed that
sedentary individuals had higher proportions of memory CD4+
T cells expressing CD45RO and PD-1, supporting the results of
other published studies that have not taken body composition
into consideration.
It should be emphasized, that among younger adults in
particular, mixed results have been reported when investigat-
ing links between an active lifestyle and hallmarks of an aging
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Exercise, Health, and Immunity Across the Lifespan
immune system. Most investigations have been cross-sectional
in design, or have made observations between groups over
short periods. For example, one study has shown that national
standard triathletes (age range 18–36 years, n = 19), appear to
exhibit impaired thymic output, assessed by T cell receptor exci-
sion circle levels (211). Among CD4+ and CD8+ T cells, these
athletes had lower absolute numbers of naïve cells and higher
absolute numbers of memory cells compared to age-matched
less active controls (n = 16), as shown by CD45RA, CD45RO,
and CD27 expression (211). Similar observations have been
made by examining individuals in the third decade of life, show-
ing that endurance athletes, compared to less active controls,
appear to exhibit slightly larger accumulations of memory
T  cells and slightly fewer naïve T  cells, defined by CD45RA
and CCR7 expression (212). Thus, it appears that among
younger individuals (i.e., less than 40 years of age), if exercise is
undertaken at very extreme volumes, such as more than 5–10
times the amount of physical activity recommended each week
(i.e., 12–25 h per week), this might contribute toward a small
decline in naïve T cells and a small increase in memory T cells.
It is possible that these changes are due to reactivation of latent
viruses, which could be independent of immune function, and
driven by exercise-induced adrenergic activity, oxidative stress
and inflammatory cytokines (48–50). However, these results
might also be explained by fluctuations in cell numbers and cell
sub-populations in peripheral blood over time. Such changes
have been interpreted as being linked to exercise training load
(213, 214), but it is also conceivable that these changes occur
due to seasonal variation, as has been shown in non-exercise
contexts (215, 216).
Experimental Evidence in Older People: Can
Exercise Limit or Counter Aging of the Adaptive
Immune System?
Although most studies have examined associations between
biomarkers of an aging adaptive immune system in young
adults, other studies have made measurements across a broader
range of ages. For example, one study examined 102 men rang-
ing in age from 18 to 61  years (mean 39  ±  6  years) (217). It
was shown that the proportion of the CD4+ and CD8+ T  cell
pool comprising of memory cells (defined as KLRG1+CD57+
or KLRG1+CD28−) was inversely correlated with cardiores-
piratory fitness, which is largely indicative of an active lifestyle
(217). The age-associated decrease of naïve T  cells (defined as
KLRG1−CD57− or KLRG1−CD28+) and increase in memory
T cells did not withstand statistical adjustment for cardiorespira-
tory fitness, but remained significant after adjusting statistically
for body composition and Cytomegalovirus infection (217).
Thus, it was concluded that fitter individuals exhibit a smaller
age-associated decline of naïve T cells and a smaller accumula-
tion of memory T cells.
As with work examining relationships between an active
lifestyle and hallmarks of an aging adaptive immune system in
young and middle-aged adults, similar associations have been
shown in an older population of 61 men aged 65–85  years
(218). In this study, participants self-reported to be “untrained”
(n  =  15), or to lead a “moderate” training lifestyle (n  =  16;
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Campbell and Turner
taking part in team sports or running less than 6 km two to
three times per week), or an “intense” training lifestyle (n = 15;
running approximately 10 km at least 5 days per week). These
categories were confirmed with a validated physical activity
questionnaire and by measurement of cardiorespiratory fitness.
Both training groups exhibited a lower proportion of CD4+
and CD8+ memory cells (defined as CD45RA+CCR7−), but
these associations were largest and only statistically significant
among men leading an “intense” training lifestyle, suggesting
a dose–response effect of exercise. Although findings were
less clear when examining other cell subpopulations based on
CD45RA and CCR7 expression, and there were no effects of
exercise when examining CD28− cells, men in the “trained”
groups had T cells with the longest telomeres (218). Another
recent study compared 125 adults (55–79 years of age) who
maintained a high level of cycling throughout life to 75 age-
matched inactive controls (219). Within the CD4+ and CD8+
T cell pool, the frequency of naive cells (defined as CD45RA+)
was greater, and the frequency of memory cells (defined as
CD45RA-) was lower among cyclists. Extended phenotyping
revealed that CD4+ and CD8+ CCR7-CD45RA+ accumulation
was less among cyclists, but no differences were found for
CD28-CD57+ cells. Cyclists also exhibited higher frequencies
of recent thymic emigrants and regulatory B cells, lower Th17
polarization, and in plasma, higher IL-7 and lower IL-6 (219).
Despite these findings, suggesting a beneficial effect of leading
an active lifestyle on immunosenescence among older adults,
there is some inconsistency in the literature. For example,
comparing elderly athletes (n = 12, approximately 74 years of
age) to less active age-matched controls (n = 26), there were
no differences in thymic output, the proportions of naïve
or memory CD4+ and CD8+ T  cells (defined with CD45RA
and CCR7 expression), or T  cell activation in response to
anti-CD3 stimulation (212). Most investigations of T  cell
immunosenescence and lifestyle among healthy elderly adults
have had cross-sectional study designs. Longitudinal studies,
or randomized and controlled trials of exercise training are
lacking and might yield promising results. For example, one
study has compared 6 months of exercise training in men and
women (n  =  28, aged 61–76  years) to a similar group who
maintained their current lifestyle (n = 20, aged 62–79 years)
(220). Using a simple immunophenotyping strategy, the results
showed that the proportion of CD4+ T cells expressing CD28
increased in the exercise group after 6 months, but not in those
who maintained their lifestyle (220).
Summary of Experimental Evidence
In summary, evidence shows that the characteristics of the
T cell pool appear to be influenced by leading an active life-
style, determined by exercise training, physical activity level,
or cardiorespiratory fitness. It seems that among both the
young and elderly, an active lifestyle is generally linked to
lower numbers and proportions of memory T cells and higher
numbers and proportions of naïve T cells (10). This summary
is partly supported by a recent systematic review, concluding
that regular structured exercise increases the number of naïve
T cells in peripheral blood at rest (221). Altogether, findings
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Exercise, Health, and Immunity Across the Lifespan
from recent studies examining relationships between an active
lifestyle and the characteristics of the T cell pool—as robust and
accepted biomarkers of immunosenescence—support obser-
vations from some cross-sectional and longitudinal studies,
showing that other measures of immune competency, which
typically decline with aging, can be improved with physical
activity or regular structured exercise (163–165). However,
further research is needed in this area that employs precise
lifestyle measurements (e.g., using wearable technology to
assess physical activity, and dual energy X-ray absorptiometry
to measure body composition) and more robust measurements
of immune competency (e.g., absolute cell counts rather than
proportions, measurements of cell function, and in  vivo
antigen challenges) while controlling for factors that drive
immunosenescence (e.g., inflammation and Cytomegalovirus
infection).
Mechanisms
Links between a physically active lifestyle with lower numbers
or proportions of memory T  cells, and higher numbers or
proportions of naïve T cells, have been hypothesized as being
driven by the acute effects of exercise bouts. For example, it has
been suggested that repeated bouts of exercise might prevent
or delay immunological aging by limiting the accumulation of
CD4+ and CD8+ antigen-experienced memory T  cell clones,
repopulating blood with antigen-inexperienced naïve T  cells
(11, 12). In this hypothesis, it is proposed that memory T cells
are frequently mobilized into blood during regular bouts of
exercise, followed by an extravasation to peripheral tissues,
where these cells are exposed to pro-apoptotic stimuli, such
as reactive oxygen species, glucocorticoids, and cytokines (11,
12). Subsequently, it is proposed that the number of naïve
T cells increases as part of a negative feedback loop governing
the number of naïve and memory cells in the immune system,
which is bolstered by exercise-induced thymopoiesis and extra-
thymic T cell development (11, 12). Supporting the mechanisms
proposed in this hypothesis, many investigations have shown
that memory T cells are mobilized into the circulation during
exercise, followed by extravasation out of the bloodstream
in the hours following (81, 123). In addition, studies in mice
show that lymphocyte apoptosis occurs post-exercise in tissues
thought to be the homing destination of mobilized cells (222).
Although some T cells mobilized by exercise might be resistant
to apoptosis, given that Cytomegalovirus-specific CD8+ T cells
express high levels of Bcl-2 (223), other work has shown
that Cytomegalovirus-specific CD8+ T  cells, are equally as
susceptible to Fas-induced apoptosis as the total pool of CD8+
T cells (224). Further, irrespective of virus specificity, studies
have shown that T cells expressing cell-surface proteins such
as CD57 and KLRG1 are more susceptible to H2O2-induced
apoptosis than total lymphocytes and naïve T cells (225, 226).
Thus, the concept of exercise directly countering memory
T cell accumulation is supported by evidence from human and
animal studies.
It is unknown whether triggering apoptosis among expan­
ded clones of memory T  cells specific for viruses such as
Cytomegalovirus is advantageous. For example, in a transplant
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Campbell and Turner
setting, Cytomegalovirus disease occurs when T  cells fail to
provide antiviral control (227) and a robust pro-inflammatory
response to Cytomegalovirus has been associated with longer
survival in the elderly (228). However, it remains to be deter-
mined what proportion of the T cell pool needs to be specific
for Cytomegalovirus to limit viral reactivation. Infection with
Cytomegalovirus results in approximately 10% of the CD4+ and
CD8+ T cell pool becoming specific for this virus (229), although
large inter-individual differences exist. For example, it has been
reported that 23% of the CD8+ T cell pool can become specific
for a single Cytomegalovirus epitope (223). Traditionally, it has
been considered disadvantageous for such a large proportion of
the T cell pool to be specific for one virus. This view is linked
to another age- or infection-associated change that occurs in
parallel—a fall in the numbers and proportions of naïve cells—
which has been interpreted as limiting capacity to engage novel
antigens. These interpretations are based upon two assumptions.
First, there is an upper limit to the size of the immune system,
and second, thymic output is negligible after adolescence (230).
Thus, it has been proposed that antigen-inexperienced naïve
T cells could be “used up” due to ongoing differentiation into
antigen-experienced memory T cells that “fill up” immunological
“space” (230). It has also been proposed that this accumulation
of antigen-experienced memory T cells leads to “squeezing out”
of T cells targeting less dominant viruses leading to loss of viral
control (231). This concept of a fixed amount of immunological
space has since been debated (232, 233) and thymic output is
now known to persist, albeit reduced, up until around 70 years
of age (234). However, even if removal of some memory T cells
is not essential for maintaining an effective T cell pool, assuming
these cells contribute to systemic inflammation, their removal
might limit “inflammageing” (230). Despite uncertainties over
the susceptibility of memory T  cells to undergo apoptosis, or
whether it is advantageous to stimulate their removal, it seems
that exercise-induced immune cell death in the tissues has
relevance to other processes. For example, apoptotic cells and
cell debris stimulates hematopoietic stem cell mobilization
into blood (95) perhaps promoting trafficking to the thymus
or extrathymic sites facilitating output of naïve T  cells (235).
Additional support for exercise stimulating production of naïve
T  cells is provided by work showing that contracting skeletal
muscle produces IL-7 (236) which might increase thymic mass
and function (237).
A physically active lifestyle might also counter T cell immu-
nosenescence indirectly, perhaps by limiting adipose tissue
accumulation and dysfunction that occurs with aging and obesity
(174, 238, 239). Indeed, obesity has been linked with impaired
lymphocyte proliferation (240), shorter leukocyte telomere length
(241), and a skewing of the T cell pool toward a regulatory and
Th2-phenotype (242). In addition, large expansions of differenti-
ated αβ T cells and γδ T cells have been shown among people with
obesity, with γδ T  cells exhibiting impaired antiviral function
(243–245). It is generally accepted that repeated stimulation with
antigens from Cytomegalovirus drives immunosenescence (185,
186, 193, 194). With obesity, adipose tissue is the primary source
of pro-inflammatory cytokines and reactive oxygen species (174,
246) which can reactivate Cytomegalovirus directly (48, 49).
Frontiers in Immunology  |  www.frontiersin.org
Exercise, Health, and Immunity Across the Lifespan
Thus, exercise might limit T cell immunosenescence by decreas-
ing visceral and subcutaneous adipose tissue (238), providing a
potent anti-inflammatory and anti-oxidative stimulus (247, 248).
In turn, lower systemic inflammation and better redox balance
might limit viral reactivation, reducing stimulation with antigens
from viruses such as Cytomegalovirus. In addition, T cell dysfunc-
tion might also be prevented, in part, by limiting reactive oxygen
species production (249).
In summary, leading a physically active lifestyle appears to
limit the age-associated changes to the cellular composition
of the adaptive immune system, but the mechanisms are yet
to be determined. Exercise might counter the expansion of
memory T  cells directly, which is desirable assuming these
cells contribute to systemic inflammation and not all are
required to control latent viruses. Limiting the expansion of
memory T cells also assumes the “size” of the immune sys-
tem is fixed, the capacity to produce antigen-naïve T cells is
limited, and these constraints contribute to immune decline
in the elderly. However, exercise might affect memory T cell
accumulation indirectly, by reducing viral reactivation, or
preventing T  cell senescence, by controlling adipose tissue
deposition and dysfunction that drives inflammation and
oxidative stress with aging and obesity.
CONCLUDING REMARKS
Contemporary evidence from epidemiological studies shows
that leading a physically active lifestyle reduces the incidence
of communicable (e.g., bacterial and viral infections) and non-
communicable diseases (e.g., cancer), implying that immune
competency is enhanced by regular exercise bouts. However, to
this day, research practice, academic teaching, and even physi-
cal activity promotion and prescription continues to consider a
prevailing myth that exercise can temporarily suppress immune
function. We have critically reviewed related evidence, and conclude
that regular physical activity and frequent exercise are beneficial,
or at the very least, are not detrimental to immunological health.
We summarize that (i) limited reliable evidence exists to support
the claim that exercise suppresses cellular or soluble immune
competency, (ii) exercise per se does not heighten the risk of
opportunistic infections, and (iii) exercise can enhance in vivo
immune responses to bacterial, viral, and other antigens. In addi-
tion, we present evidence showing that regular physical activity
and frequent exercise might limit or delay immunological aging.
We conclude that leading an active lifestyle is likely to be benefi-
cial, rather than detrimental, to immune function, which may
have implications for health and disease in older age.
AUTHOR CONTRIBUTIONS
JC and JT contributed equally toward literature searching and
retrieval, the ideas and interpretation of the studies described,
drafting and revision of the manuscript, and approval of the final
version to be published. JT and JC both agreed to be accountable
for the work in ensuring that questions related to the accuracy or
integrity of any part of the work are appropriately investigated
and resolved.
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Campbell and Turner
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Conflict of Interest Statement: The authors declare that the research was con-
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